The overall goal of the research described in this proposal is to further elucidate the functions and mechanism of action of the extracellular matrix protein biglycan in regulating the dystrophin and utrophin protein complexes during development. In muscle, biglycan is associated with the dystrophin associated protein complex (DAPC). Mutations in genes encoding members of the DAPC cause a range of muscular dystrophies including Duchenne Muscular Dystrophy (DMD), which is caused by mutations encoding the dystrophin gene. Far less is known about the utrophin protein complex, but it is of great interest due to the therapeutic value it may play for DMD. Previous work from our lab has shown that biglycan binds to members to members of the DAPC, including the dystroglycans and sarcoglycans. Young adult (5wk old) biglycan null mice display a selective reduction in nNOS, dystrobrevin, and syntrophin. Collectively these proteins are termed the NODS complex and employ a signaling function within the DAPC. Intramuscular injection of recombinant biglycan protein into biglycan null mice restores the sarcolemmal association of members of the NODS complex. Our preliminary results have suggested a relationship between biglycan and utrophin, the autosomal homologue of dystrophin. Delivery of recombinant biglycan protein to mdx mice, a murine mode) of DMD, results in utrophin upregulation at the sarcolemma. These findings suggest that biglycan plays a role in regulating utrophin and NODS complex sarcolemmal association and protein expression. The ability of biglycan to restore DAPC-like complexes, in the absence of dystrophin, via its ability to recruit utrophin to the sarcolemma suggests that it may serve as a therapy for DMD. However, the mechanisms by which biglycan exerts its effects are unknown. To continue to address the role of biglycan during development of both the dystrophin and utrophin protein complexes I propose the following aims: (1) to determine if biglycan regulates the expression of members of the NODS complex and of utrophin during development and (2) to characterize the role of biglycan in the expression and assembly of the dystrophin and utrophin protein complexes.
Duchenne Muscular Dystrophy (DMD) is the most common form of muscular dystrophy for which no effective therapies exist. Biglycan potentially acts to regulate the structure of the DAPC and the function of its components. Understanding the mechanisms of this regulation will allow us to explore possible therapies for DMD.
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